Nu, nu-disubstituted-beta-haloalkylamines



Patented June 3, 1952 UNITED STATES PATENT OFFICE N ,N-DIS-UBSTITUTED-BE TA-HALO- ALKYLAMINES James F. Kerwin and Glenn E. Ullyot, Philadel- Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application September Serial No. 183,094

in which:

Y and Y are members of the group consisting of hydrogen, alkyl groups containing not more than 4 carbon atoms, hydroxy, methoxy and chlorine.

R. and R are members of the group consisting of hydrogen and methyl.

X is a member of the group consisting of chlorine and bromine.

Where hereinafter the symbols Y, Y, R, R and X are mentioned, they will indicate the substituents indicated for them in connection with the above general formula.

Th organic and inorganic salts contemplated by this invention include by way of example salts of the bases formed with organic acids such, for example, as glycolic, oxalic, maleic, camphorsulfonic, etc. and inorganic acids such as, for example, sulfamic, hydrochloric, hydrobromic, sulfuric phosphoric, etc. More specifically, the inorganic and organic salts will be such as are prepared with inorganic and organic acids having an ionization constant not less than 1 l0- at 18 C.

The compounds in accordance with this invention and as identified by the above structural formula may be prepared variously by one of four general methods, from the following gen eral description of which procedure for the preparation of all of the several compounds will be apparent to those skilled in the art.

2 The compounds used as starting materials for the synthesis of compounds of this invention are either known substances or, being made obvious, can be prepared by well known methods.

METHOD A A propylene halohydrin or propylene oxide is added to the sodium salt of a phenol of the type in refluxing alcohol to form the alcohol having the formula:

-o-cnr-in-cm This same alcohol may also be obtained by reducing the corresponding ketone with hydrogen in the presence of a suitable halogenation cata lyst, as, for example, platinum, palladium, or activated nickel (reference: Hurd & Perletz: J. A. C. S. 68, 38 (1946).

The halide, formed by treating the alcohol with a suitable halogenating agent such as, for example, thionyl chloride, thionyl bromide, etc., is added to ethanolamin or isopropanolamlne. When the resulting mixture is heated, the temperature employed depending upon the reactivity of the halide chosen, there is formed the N-substituted amino alcohol of the formula:

In this process it is advantageous to employ an excess of the primary amino alcohol.

Th phenoxyalkyl or substituted phenoxyalkyl group is introduced into the molecule by heating Finally, the hydroxyl group of the amino alcohol is replaced by a halogen radical X, as in the general formula above. a halogenating agent such as thionyl chloride or thionyl bromide to yield the product in the dorm: of its hydrohalide salt. An excess of thionyl" halide may be employed as solvent for this reaction or chloroform, benzeneor othersuitable solvent may be used.

METHOD B The secondary amino alcohol produced' as in" Method A above may also be obtained by means of the following reaction:

METHOD. C

I The. ketones used" as starting materials in Method B mayalso be used inthe' reaction which may becarried out in the same manner as describedpin. Method B ab'ove.v The. secondary -Je mt nam v.th nbe ea t t e hvb iz n v ine.ha d ine t rv in. se e of .a-solvent, or. inthepresence. 01 a solvent such as. ethyl alcohol, benzene, toluene or xylene. Unless. one employs anexcess of the amine, it will be advantageous to use an acid binding The alcohol is reacted with.

agent, such as potassium carbonate, sodium bicarbonate, or magnesium oxide:

If ,;desined;,the,-tertiary amino alcohol may also be iormedby heating the secondary amine together with an ethylene or propylene oxide;

rather than utilizing the ethylene or propylene halohydrin in the reaction.

The product of this reaction may then be reactedwith a thionyl halide .as in Method A -t0 replace. the hydroxyl groupv with the. halide radical.

METHOD D.

The secondary .amine prepared inflMethod C above-may also be made by an alternative method. This involves treating a primary amine of the type with-aphenoxyalkyl jor :substitutedphenoxyalkyl aldehyde or ketone' and reducing the; resulting mixtureasadescribedgin Methodyl; above. The tertiary amino alcohol is formed fromvtheysecondaryamine by the usezof either: an .alkc'lene halohydrin or an alkyleneoxide-masdescribed in Method C, which amino alcohol is :trea,ted: as. in Method A to form the correspondinghalide.

The following: examples. will be illustrative: of

- the-various typmmi' compounds-andof'speclflc compounds-in accordance :with'the 'inventionzand procedure for their preparation and. will,-, it.-,is believed, serve to make fully apparentall ot the compounds embraced. by the general formula given above and the preparation thereof; respectively, itbeing-noted that the utility indicated for the several compounds flows fromtheelementsof" the general structure common to all oi them Exemplar N ph nq on nyl J- nh ycth F'- chlorethylamine hydrochloride:

yawn-one This compound will be prepared by Method A above as follows:

Step 1.-In a 500 ml. flask equipped with gas inlet tube, dropping funnel-and reflux condenser is placed 139 g. of l-phenoxy-Z-propanol. A stream of dry air is bubbled through the alcohol while g. of thionyl chloride is added dropwise with external cooling. The stream of dry air is continued for about six hours or until most of the hydrogen chloride has been expelled and then another 55 g. of thionyl chloride is added. The reaction mixture is allowed to stand twentyiour hours, a few drops of pyridine are added and the mixture heated four hours on the steam bath. The cooled reaction mixture is poured into water, the crude product is washed with dilute sodium bicarbonate solution and finally taken up in benzene. The benzene is distilled at ordinary pressure and the residue distilled in vacuo to yield -70% of 1-phenoxy-2-chloropropane, B. P. 93-94 C./5 mm.

Step 2. To 494 g. of ethanolamine, heated to approximately 150 C. in a 500 ml. flask equipped with stirrer, condenser and dropping funnel, is added 465 g. of 1-phenoxy-2-chloropropane with mechanical stirring. The reaction mixture is then heated to reflux for three hours, cooled and poured into a liter of water. The organic layer is extracted into ether and the ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is then made alkaline with 40% sodium hydroxide solution and the organic base is extracted into ether. Removal of the ether leaves N-(phenoxyisopropyl) -ethanolamine which, after recrystallization from hexane, melts at 70.5-72 C.

A mixture of 48 g. of N-(phenoxyisopropyD- ethanolamine and 25 g. of phenoxyethyl bromide is heated at C. for three hours and then heated gradually to C. over a four hour period. The cooled mixture is dissolved in 100 ml. of benzene and extracted thrice with Water. Distillation of the benzene layer yields N-phenoxyisopropyl N-(phenoxyethyl) -ethanolamine which distills at -167" C..at 0.2 mm.

Dry hydrogen chloride is introduced into a solution 01' 29g. of the above amino alcohol in 100 ml. of dry chloroform until the solution is acid. The acidified solution is cooled while 13.4 g. of thionyl chloride is added and, after the addition is complete, heated to reflux for 1 /2 hours. lization of the residue from alcohol and ether gives N-phenoxyisopropyl N phenoxyethyl-flchlorethylamine hydrochloride which melts at 99.5-100.5 C. Emample 2 N,N-bis-(phenoxyisopropyl-e-chlorethylamine hydrochloride Thiscompound will be prepared by Method C described above. 24 g. of phenoxyacetone and 24 g. of fi-phenoxyisopropylamine are heated at 110-120" C. for 2 hours. The ketimine thus formed is dissolved in alcohol and hydrogenated with platinum catalysts at three atmospheres and 65 C. The catalysts and solvent are removed and the residue redistilled to recover bis- (pgphenoxyisopropyl)-amine, B. P. 160-162 C. at 0.2-0.3 mm. c

28 g. of the secondary amine, 1.8 g. of water and 8L8 g. of ethylene oxide are heated under pressure at 150 for six hours[ The reaction mixture is taken'up in ether, dried and distilled Removal of the solvent and recrystalto yield bis (fl-phenoxyisopropyl) aminoethanol.

2 g. of bis-(fi-phenoxyisopropyl)-aminoethanol and 0.7 g. of thionyl chloride in 25 ml. of chloroform are refluxed for one-half hour and the solvent is evaporated under reduced pressure, leaving N,N bis-(,S-phenoxyisopropyl) -fl-chlorethylamine hydrochloride as an oily residue. The free base is formed by treating the hydrochloride with aqueous sodium bicarbonate solution and extracting with ether. A crystalline sulfate salt, M. P. 168.5 C. is formed by adding sulfuric acid to the other solution of the base Example 3 N-(o-methylphenoxyisopropyl)-N phenoxyethyl-fl-chloroethylamine hydrochloride:

One mole of o-cresol and 300 ml. of alcohol are placed in a flask fitted with stirrer, reflux condenser and dropping funnel. A solution of 40 g. of sodium hydroxide in 40 ml. of water is added, the solution of sodium o-cresoate is heated to refiuxing and one mole of propylene chlorohydrin is added with stirring over a two hour period. After the addition is complete, the reaction mixture is cohol is removed by distillation under diminished refluxed an additional five hours. Most of the alpressure, the residue is dissolved in benzene and washed several times with water and then with 10% sodium hydroxide solution. The benzene is then distilled and the residue is distilled in vacuo. l- (o-methylphenoxy) -2-propanol distills at 86-88 C./2 mm. The p-nitrobenzoate ester melts at 95.5-96 C.

The end product is formed from l-(o-methylphenoxy) -2-propancl as in the manner described under Example 1 by halogenation with thionyl chloride to form l-(o-methylphenoxy) -2-chloropropane, B. P. 94-95" C./3 mm., which, in turn, is reacted with ethanolamine to form the secondary amino alcohol N-(o-nethylphenoxy-isopropyD-ethanolamin'e, M. P. 57.5-59 C. The phenoxyethyl group is introduced by heating the secondary amino alcohol with phenoxyethyl bro mide as in Example 1. The resulting tertiary amino alcohol is then treated with thionyl chloride to produce. N- (o-methylphenoxyisopropyl) N-phenoxyethyl-fJ-chloroethylamine hydrochloride.

' Example 4 N (p-isopro pylphenoxyisopropyl) -N- (o-methylphenoxyethyl) -B chlorethylamine hydrochloride:

CH3 N-CHz-CHr-CLHCI In this preparation the procedure of Example 3 will be followed using as a starting material p-isopropylphenol in place of o-cresol. The phenol is converted by means of sodium hydroxide to the sodium salt which is refluxed with propylene chlorohydrin to obtain p-isopropylphenoxy isopropanol.

.The'm'mduct-N (p isomilphenoxyimmwhs ethanolamine is formed in the same manner-ass describedin. Example-1 1 by ihalogenation .0! the p isopropylphenoxyisopropanol with thionyl chloride toformv p-:-.isopml ylphenoxyu isopropyl chloride which :is :reacted' witlrcthanolamine to tormlthe-secondary-amino alcohol. The second ary amino alcohol will .bereacted withjo'rmflthyle phenoxyethyl: bromide 2m place of aphenoxyethyl bromide 1 in the: same manner as: described Example 1. Theaflnal step, halogenatiom with thionyl" chloride isconducted- .as described i above to convert the resulting: tertiary amino valcohol to N-(p-isopropylphenoxyisopropyl) -N- (o-methylphenoxyethyl) -;8-chlorethylamine hydrochloride;

Example 5 N (phenoxyisopropyl) -N- (m-hydroxyphenoxyethyl) -fi-chlorethylamine hydrochloride:

I OH

N-. phenoxyisopropyl) -ethanolamine:is;formed as an intermediate in the procedure of Example 1. Anexcess'ofthiscompound isreacted with m-hydroxyphenoxyeth' ylbromide in place of phenoxyethyl! bromide as described in Example, 1. The: resulting tertiary I amino: alcohol is :treated with;thionylchlorideto produce.:N- (phenoxyisopropyl) -N (m-hydroxyphenoxyethyl) -Bechlorethylamine' hydrochloride;

Example *6 vN'-v (phenoxyisopropyl -N-' (o -.metho'xyphenoxy.- ethyl) -B-chlorethylamine hydrochloride:

N- (phenoxyisopropyl) -ethanolamine is Iormed asanwintermediate in the procedure of Example 1. This compound is reacted with oemethoxy= phenoxyethyl bromide in place of I pheno'xyethyl bromide. as described linExample 1. The result.- ing tertiaryamino. alcohol istrea'ted with thionyl chloride to produceiN-(,phenoxyisopropyllNe(o? methoxyphenoxyethyl) B- chlorethylamine jhyf drochloride.

Example] N-(phenoxyisopro'pyl) N (p-chlorophenoxy ethyl) -fi-chlorethylamine hydrochloride:

N-CHFGHr-CLHUI,

N-(phenoxyisopropyl) -ethanolamine is formed as an intermediate in the procedure of Example 1. This compound; is reacted; with pechlorophenoxyethyl chloride in placea-otjphenoxyethyl bromide :as described: ixrExamplel The'resulting tertiary amino alcohol is trcatediwith thionyl chloride to produce N- (phenoxyisopropyl') i-N-s pchlorophenoxyethyl)-p-chlorethylamin hydrochloride.

EmampleJ N (o;-.se'c --sbut'ylp henoxy isopropyl) N one. noxyeth'yl fl-chloroethylamine hydrochloride The procedure of Example '1"wiilbeiolloweddn tertiary; amine alcohol convertedto -the:ha'iide by-reaction with thionyl'chloride:

Example 9 N phenoxyisopropylN-phenoxyethylel aminoe 2-chloropropane hydrochloride:

I'nWthe preparation of thiscompp'und, their phenoxyisopropyl 2 chloropropane reacted with isopropanolamine, instead of eth'anolamine. under the-conditions described in Example The resulting secondary. aminoalcohol. M. P. 69411"v C. is treated with phenoxyethyl bromide to prepare vthe N-phenoxyethyl derivative. The resulting tertiary amino alcohol is convertedto the halide by treatment with thionyl chloride.

Example 10 N phenoxyisopropyl-N- (m-methoxyphenoxy isopropyl) -fi chloroethylamine hydrochloride-r Equimolar amounts of fi phenoxyisopropylamine and m-methoxyphenoxyacetone are heat- 'ed ati110 C: until-the water-formed iszdriven ofl'l Tho -reaction 'mixture is then diluted with alcohol' omd subjected to catalytic hydrogenation with platinum catalyst at $3 atmospheres pressure. and: 65 'C'. The secondary amine-thus formed'iis recovered I by: distillation :atter removing the catalyst and solvent: Heating the sec- 'ondary amine withan excess lotethyleneoaide under pressure at as described-iniExample' z, introduces the N-(fl-hydroxyethyl)group. The

product is distilled and then'itreated with thionyl chloridein chloroform solution to form N-phenoxyisopropyl-N-(m methoxyphenoxyisopropyl-i fis-chloroethylamine-,hydrochloride;-

awado'i 9 Example 11 N-phenoxyisopropyl N (o-methylphenoxyisopropyl) --chloroethylamine hydrochloride:

Q-O-CEh-C-CH:

This compound is prepared in the same manner as Examples 2 and 10. p-phenoxyisopropylamine and o-methylphenoxyacetone are heated together at 110-120 to form the ketimine which is then reduced catalytically over platinum catalyst. The secondary amine is 'heated under pressure with ethylene oxide and the resulting tertiary amino alcohol is reacted with thionyl chloride in chloroform solution to form the end product.

Example 12 N-phenoxyisopropyl-N-phenoxyethyl ,3 bromoethylamine hydrochloride:

N phenoxyisopropyl N (phenoxyethyl) ethanolamine, an intermediate in the preparation of Example 1, is dissolved in chloroform and dry hydrogen bromide is introduced until the solution is acid. Then a slight excess of thionyl bromide is added and the solution is refluxed for one hour. Removal of the solvent leaves N- (phenoxyisopropyl) -N-(phenoxyethyl) B bromoethylamine hydrobromide which is recrystallized from alcohol and ether.

Example 13 N, N-bis-(phenoxyisopropyl) ,B-bromoethylamine hydrobromide:

CHa

N, N-bis-(phenoxyisopropyl) -aminoethanol, an intermediate in the preparation of Example 2, is

treated with thionyl bromide in chloroform solution as described in Example 12.

In the foregoing examples hydrochlorides and hydrobromides according to this invention are exemplified. However, it will be understood and readily appreciated by those skilled in the art that the foregoing examples will illustrate the structure of organic or inorganic salts generally and will serve as specific examples of those organic and inorganic salts heretofore mentioned specifically by the writing in the several foregoing illustrative structures of the chemical symbols for the several acid groups heretofore specifically mentioned or of the acid group of any other desired organic or inorganic acid for the HCl or HBr in the several foregoing examples, respectively.

It will similarly be self-evident to those skilled in the art that in the foregoing examples illustrative of the production of chloride hydrochlorides by the procedures described, bromide hydrobromides will be produced with the use, for example, of thionyl bromide in place of thionyl chloride in the final step. Thus, the foregoing specific examples of chloride hydrochlorides serve as specific examples of bromide hydrobromides by 10 simply replacing CLHCl in the several formulae with Br.HBr.

The foregoing examples illustrate the salts contemplated by this invention. The bases contemplated by this invention according to the broad and more particular structural formulae herein disclosed are specifically exemplified as will be obvious to anyone skilled in the art by reference to the foregoing specific examples with the removal from the structures illustrated thereby of the acid group, i. e., I-ICl or HBr.

As will be apparent, the organic and inorganic salts contemplated by this invention will be prepared from the bases in a manner usual and well known to those skilled in the art, as by neutralizing the bases with organic or inorganic acids.

The bases contemplated by this invention will be formed by carefully interacting the salts contemplated by this invention and herein exhaustively exemplified with one molecular equivalent of a strong alkali such, for example, as sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like, in aqueous solution say, for example, a 1-10% solution at room temperature or below and the bases so liberated are isolated with the aid of a water-immiscible solvent such as ether or benzene. The preparation of free bases from salts is illustrated under Example 1.

The compounds contemplated by this invention will be variously optically inactive or optically active and it will be understood that the optically inactive and optically active forms of the compounds contemplated by this invention are all included within the scope of this invention.

The various types of compounds having the structure embodying this invention as illustrated by the above specific examples and examples of the various types of compounds will be readily prepared by the general methods of preparation described above as exemplified by the description of the preparation of the several specific examples. The starting material for the preparation of any given compound within the structure contemplated by this invention will be found among known compounds, or, its structure being obvious with reference to any particular compound desired to be prepared. will be readily prepared by known methods.

This application is a continuation-in-part of application filed by us Serial No. 97,926, filed June 8, 1949, now abandoned.

What is claimed is:

1. A compound of the class consisting of a free base and its acid addition salts, the free base having the formula:

in which Y and Y are members of the group consisting of hydrogen, alkyl groups containing not more than 4 carbon atoms, hydroxy, methoxy, and chlorine; R and R are members of the group consisting of hydrogen and methyl; and X is a member of the group consisting of chlorine and bromine.

2. The compound having the structure: 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA: 